Drug-sensitiveFGFR2mutations in endometrial carcinoma

Abstract

Oncogenic activation of tyrosine kinases is a common mechanism of carcinogenesis and, given the druggable nature of these enzymes, an attractive target for anticancer therapy. Here, we show that somatic mutations of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene, FGFR2, are present in 12% of endometrial carcinomas, with additional instances found in lung squamous cell carcinoma and cervical carcinoma. These FGFR2 mutations, many of which are identical to mutations associated with congenital craniofacial developmental disorders, are constitutively activated and oncogenic when ectopically expressed in NIH 3T3 cells. Inhibition of FGFR2 kinase activity in endometrial carcinoma cell lines bearing such FGFR2 mutations inhibits transformation and survival, implicating FGFR2 as a novel therapeutic target in endometrial carcinoma.endometrial cancer ͉ fibroblast growth factor receptor 2 ͉ oncogene ͉ targeted therapy ͉ tyrosine kinase T yrosine kinases play a major role in transduction of proliferative signals and can become oncogenic when deregulated by somatic mutation (1). Somatically altered tyrosine kinases have proven to be tractable therapeutic targets in several tumor types; examples of successfully targeted tyrosine kinases include ABL1 in chronic myeloid leukemia (2), KIT in gastrointestinal stromal tumors (3), ERBB2 in breast cancer (4), and EGFR in non-small-cell lung cancer (5-7). The tyrosine kinase family has not been exhaustively studied in human cancer, and it is likely that additional tyrosine kinase therapeutic targets remain to be discovered.The fibroblast growth factor receptor (FGFR) tyrosine kinase family, which is comprised of four kinases that differentially respond to 18 FGF ligands (8, 9), has long been implicated in cancer. Translocations involving FGFR3, and activating somatic mutations in FGFR3, have been identified in multiple myeloma patients (10, 11), and translocations of FGFR1 have been found in patients with 8p11 myeloproliferative syndrome (12). Isolated cases of a missense mutation of FGFR4 in a lung adenocarcinoma patient and missense mutations of FGFR2 in a lung squamous cell carcinoma patient and gastric cancer patient have also been reported (13,14). In addition to these documented examples of somatic mutation of FGFR family members in cancer, a germ-line polymorphism in the second intron of FGFR2 was found to be associated with breast cancer in genomewide association studies (15,16).FGFR1-FGFR3 are characterized by alternative splicing of the mRNA encoding the third Ig-like repeat in the extracellular ligand-binding domain. This differential splicing determines ligand specificity such that isoforms expressed primarily in epithelial cells (IIIb) preferentially bind FGF ligands expressed by mesenchymal cells, and isoforms expressed primarily in mesenchymal cells (IIIc) preferentially bind FGF ligands expressed by epithelial cells (17)(18)(19). Alteration of this restricted expression pattern can lead to oncogenic transformation (20). Mutations in FGFR2 and FGF...

FGFR2 alterations in endometrial carcinoma

“…The frequency of FGFR2 mutations in this series (6.45%) is a little bit lower than that of previous series (10-12%). [13][14][15] However, the number of cases tested for FGFR2 mutations is smaller than that of other series. It is worth mentioning that our series has the additional value that the cases had been previously tested for microsatellite instability, as well as mutations of KRAS, PTEN, PIK3CA and CTNNB1.…”

“…Moreover, somatic mutations in the receptor tyrosine kinase FGFR2, identical to the germline mutations associated with craniosynostosis and skeletal dysplasia syndromes, have been recently detected in 10-12% of endometrial carcinomas, particularly in endometriod endometrial carcinomas (16%). [13][14][15] The somatic mutations included the S252W and P235R changes, which are associated with the Apert syndrome, the N549K and K659M, which are associated with Crouzon syndrome, as well as the N550K change. 31 Interestingly, FGFR2 and K-RAS FGFR2 in endometrial cancer mutations were mutually exclusive events, whereas mutations in FGFR2 and PTEN frequently coexisted.…”

“…Recently, some investigators have suggested that alterations in fibroblast growth factor receptor 2 (FGFR2) could be added to the molecular-specific features of endometrioid endometrial carcinomas. [13][14][15] FGFR2 is of special interest, as it is a possible target for therapeutic approaches, and FGFR2 inhibitors are currently under consideration in clinical trials for several types of solid tumors. FGFR2 belongs to fibroblast growth factor receptor (FGFR) tyrosine kinase family that comprises four different transmembrane kinases (FGFR1-FGFR4) and their alternative spliced isoforms.…”

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…For example, the targetable S252W mutation has been found that in 12% of endometrial cancer cells (Dutt et al, 2008).…”

Improved survival related to changes in endometrial cancer treatment, a 30-year population based perspective

“…96 Other oncogenes have also been reported as altered in endometrial cancer; Drug sensitive mutations in the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene have been reported in 12% of endometrial carcinomas. 119 Nuclear accumulation of ȕ-catenin (CTNNB1), only partially explained by mutations, is detected more frequently in Type I compared to Type II cancers. 120 Growth differentiation factor-15…”